Elemental gold was believed in ancient times to have various curative properties. However, in the 1960s the effectiveness of simple inorganic gold salts administered intravenously was demonstrated in the treatment of rheumatoid arthritis. Subsequently, aurothiomalate and aurothioglucose administered in parenteral form were found to be more effective. These are water soluble complexes containing approximately 50% of gold by weight and having thiolate ligands. Gold thiopolypeptide has also been injected. Auranofin, a lipid soluble complex containing approximately 29% of gold by weight and having a phosphine and a sulphur ligand, has been administered orally.
Gold compounds (which term is herein used generally to embrace complexes in which gold is chelated or bound to one or more ligands, organo-gold compounds, inorganic gold compounds and salts thereof) have thus hitherto been administered for therapeutic purposes only by the parenteral or by the oral route and for the treatment of asthma, tuberculosis, pemphigus vulgaris, various forms of arthritis, cancer and infection.
Despite established clinical efficacy, the mechanism of action of gold compounds in the treatment of the above conditions is unknown, although it is appreciated that different chemical forms of gold have varying efficacy with respect to treating the above disorders.
Gold is a transition state metal that is capable of forming complexes in oxidation states I and III, namely: ##STR1##
The chemistry of gold compounds is complicated by the tendency of many compounds to form complex polymers.
Another complication is that gold compounds may undergo extensive modification in the body to produce the active species.
Finally there appears to be no correlation between blood levels of the various gold compounds and biological activity.
The biological activity of gold compounds is not determined solely by the presence of gold itself but also depends on:
a. the oxidation state (I or III) PA1 b. the degree of polymerization PA1 c. the types of ligands PA1 d. the stereochemistry of the molecule PA1 a. modulation of humoral and cell-mediated immunity, PA1 b. inhibition of the formation of immune complexes and/or the transmitter substances released as a consequence of the immune complex formation, PA1 c. inhibition of the formation and/or release of lysosomal enzymes, PA1 d. inhibition of the formation and/or action of prostaglandins, PA1 e. inhibition of the proliferation of synovial and other cell types including cancer cells, PA1 f. modulation of copper and zinc metabolism, PA1 g. enzyme inhibition.
Suggested mechanisms for the action of gold drugs include:
Orally administered auranofin exhibits protracted blood levels of gold in comparison with parentally administered gold compounds and is minimally retained in tissue. Both the parenteral and oral routes of administration have been known to produce severe renal, haematological and other adverse effects including skin and mucuous membrane lesions in some cases. Severe gastrointestinal upsets frequently occur following the use of oral gold.
It is known that synovial membrane, particularly when inflamed, may show selective uptake of injected or orally administered gold initially, after which it is distributed to the other tissues.
An example of selective activity is shown by auranofin which possesses greater affinity for penetration of lymphocyte membranes than do many other gold compounds, particularly those of the hydrophilic type.
In 1984 Brown et al applied a water soluble and a lipid soluble gold complex as a solution in ethanol to the skin of rats in order to measure the levels of gold absorbed into the blood stream through topical application [D. H. Brown et al. Inorganica Chimica Acta, 93 L41-L42 (1984)]. It was concluded that the lipid soluble complex was more rapidly absorbed into the blood than the water soluble complex and that blood absorption levels were comparable with oral administration. However, no corresponding tests have been reported on human skin, and studies have not shown correlation between blood levels of gold and clinical effectiveness in treatment of any of the foregoing diseases either in rats or in humans.
It has now been surprisingly discovered that gold compounds administered topically are in some circumstances significantly more effective than gold compounds administered via parenteral or oral routes while avoiding or ameliorating the disadvantages previously discussed.
It has also been surprisingly found that gold compounds administered topically are efficacious in the treatment of local and systemic inflammatory conditions such as psoriasis and rheumatoid arthritis and/or as antibacterial agents.
It has also been found that gold compounds topically applied act synergistically with corticosteroids in the therapeutic treatment of local inflammatory conditions, particularly psoriasis.